Recent large-scale synthetic biology efforts have demonstrated that it is now possible to systematically engineer biosynthetic pathways and central metabolic systems to produce massive quantities of natural products for the commodity chemicals and biofuels markets. The tools developed during these efforts, which include libraries of modular DNA constructs, defined promoters for pathway balancing, and rapid genetic engineering methods, were designed to systematically address the transcription, translation, and production of heterologous natural products in a highly efficient manner. These previous efforts, however, have focused primarily on hosts that are devoid of complex secondary metabolites such as polyketides and non-ribosomal peptides. We are developing a series of synthetic biology tools to specifically engineer bacterial genera that are rich producers of natural products in order to gain access to the metabolites encoded in cryptic gene clusters. This set of tools has the potential to revitalize natural product discovery efforts by systematicaly providing access to the molecules encoded by this important source of untapped chemical diversity.